Neurostimulation has become the new frontier in dry eye therapy, now that scientists know the trigeminal nerve is a critical factor in ocular surface health and symptomatology. In fact, the nerve plays a multifactorial role: it can become fatigued (often due to misalignment), causing dry eye symptoms, headaches and neck pain; it maintains the trophic supply to the cornea, preventing epithelial breakdown; and, when stimulated, it can also promote tear production. New products are taking advantage of the latter function to help dry eye patients produce natural, lubricating tears instantly. 

A Novel Pathway

The parasympathetic nervous system (PNS), via the trigeminal parasympathetic pathway, controls tear film homeostasis by innervating the lacrimal functional unit (LFU), which includes the cornea, conjunctiva, lacrimal glands, meibomian glands and goblet cells.1-3 The PNS is easily accessed through the nose, and research shows 34% of basal tear production is due to sensory stimulation from inhaled air through the nasal passage.4  

This patient exhibits significant meibum secretion after using the iTear100 neurostimulator.

This patient exhibits significant meibum secretion after using the iTear100 neurostimulator. Click image to enlarge.

Studies show that nasal neurostimulation affects all parts of the LFU and increases basal tears that have the same composition as the patients’ naturally occurring basal tears.5,6,8 This includes stimulation of the lacrimal glands, resulting in aqueous production and the goblet cells that secrete gel-forming mucins, such as mucin MUC5AC. The goblet cells mainly use apocrine methods; when they receive neural stimulation, they release all of the contents of their secretory granules at once. Intranasal neurostimulation also can change meibomian gland activity and lipid layer thickness with eight minutes of use.5-7 

Devices and Drops

Two therapies will soon make neurostimulation a viable treatment option for dry eye patients: the iTear100 (Olympic Ophthalmics) and verenecline (Oyster Point Pharma).

The iTear100 was FDA approved on May 1, 2020—just as Allergan discontinued its TrueTear neurostimulation device. Unlike TrueTear, which was an intranasal device that delivered small electrical currents to sensory neurons of the nasal cavity—the iTear100 is an electromechanical nerve stimulator applied externally. It is indicated for temporary use (up to 30 days) to increase acute tear production via vibratory stimulation of the external nasal nerve in adults. As with TrueTear, it also requires a prescription by an eye care provider. 

Patient’s apply the handheld, noninvasive device to the soft tissue fold on the outside of the nose for up to 30 seconds per side to activate the trigeminal parasympathetic pathway via a sonic frequency. 

Patients can use it as needed throughout the day and after one month the device requires reactivation. Currently, the patient can exchange the device through the company or their doctor’s office; in the near future, the patient will receive a reactivation code electronically or via an app, at the discretion of the eye care practitioner. 

In the clinical studies, Schirmer’s scores, fluorescein staining, tear break-up time and meibomian gland scores all improved statistically—and immediately—over the intermediateterm and long-term (180 days). Furthermore, Ocular Surface Disease Index scores showed statistical improvement at every study visit. Safety and patient comfort scores showed a favorable risk-benefit ratio with only 3% of the study population reporting adverse events such as sneezing, tickling or headaches, and 1% noted nasal pain. 

This technology is a wonderful new option to add to your armamentarium, because our natural tear secretion is far more complex and potent, containing nerve growth factors, hundreds—if not thousands—of proteins, mucins and lipids. Patients who state they frequently rely on artificial tear use may be able to use neurostimulation to decrease their reliance on artificial tears (44.2% of patients in the study) or eliminate them (23.3%) altogether. 

It’s good to see a new neurostimulation device on the market, as many patients who had success with TrueTear are looking for an alternative. The external application of the iTear100 makes it an easy treatment option for doctors, staff and patients. Training is straightforward, and patients quickly learn how to use the device by watching an online video. 

Anecdotally, I have found that providing patients the ability to boost their own tear production instantly, affecting all three components (aqueous, mucin and lipids), leads to a high patient satisfaction rate. It’s an essential tool for mild dry eye patients who do not want to instill artificial tears; it’s also useful for severe dry eye patients who still require significant artificial tear application while on other therapies.  

During the clinical trials, I personally included patients with severe dry eye and those who were recalcitrant to other therapy and observed remarkable improvements in signs and symptoms in the patients using the iTear100.  

Pharma Pipeline

An intranasal spray may soon bolster your neurostimulation options, now that Oyster Point Pharma has reported its first phase III FDA clinical trial results for verenecline intranasal spray. This preservative-free spray contains a nicotinic acetylcholine receptor (nAChR) agonist designed to stimulate the trigeminal parasympathetic pathway.

The ONSET 2 study for Oyster Point’s OC-01 drug candidate, verenecline, enrolled 758 subjects diagnosed with dry eye disease; the trial included an array of patients, including those with minimal symptoms. The subjects were randomized into three equal treatment groups: placebo (vehicle control) and two concentrations of verenecline intranasal spray, 1.2mg/ml and 0.6mg/ml). Patients were treated twice a day for four weeks.9 

TrueTear Off the Market

The first neurostimulation device approved for dry eye, TrueTear (Allergan), was recently dis-continued. Allergan is offering a full refund to patients who purchased the device in the last three years. Here’s how it works: Patients must submit proof of purchase with a consumer re-fund request form to They will then information necessary to return the device. One Allergan receives the device, it will issue a full refund within two to three weeks. Patients can get started at  

At four weeks, both active doses produced a statistically significant improvement in dry eye signs (Schirmer’s score) compared with placebo, with a mean change from baseline of 11.0mm for the 0.6mg/ml and 11.2mm for the 1.2mg/ml group (the placebo group also experienced a mean change of 5.9mm).9 

Both concentrations also met the secondary endpoint of symptom improvement, measured with the Eye Dryness Score, as soon as two weeks post-treatment.  

Adverse events were mild and transient and, given the nasal route of delivery, there were no ocular related tolerability issues. The most common adverse events included sneezing after instillation (99% of patients, all of whom listed it as mild), cough after instillation, throat irritation and instillation site irritation.     

Neurostimulation is giving us a whole new way to approach dry eye therapy. For patients who have exhausted traditional therapies, it might provide the relief they have been looking for, and for those who rely only on artificial tears, it can provide a better quality tear. Even for those with mild symptoms, the novel pathway could help relieve those symptoms when they crop up. Keep an eye out for the new device and the nasal spray on the way.

Note: Dr. Karpecki consults for companies with products and services relevant to this topic.

1. van der Werf F, Baljet B, Prins M, Otto JA. Innervation of the lacrimal gland in the cynomolgous monkey: a retrograde tracing study. J Anat. 1996;188(Pt 3):591-601.

2. LeDoux MS, Zhou Q, Murphy RB, et al. Parasympathetic innervation of the meibomian glands in rats. Invest Ophthalmol Vis Sci. 2001;42(11):2434-41.

3. Dartt DA, McCarthy DM, Mercer HJ, et al. Localization of nerves adjacent to goblet cells in rat conjunctiva. Curr Eye Res. 1995;14(11):993-1000.

4. Gupta A, Heigle T, Pflugfelder SC. Nasolacrimal stimulation of aqueous tear production. Cornea. 1997;16(6):645-8.

5. Gumus K, Schuetzle KL, Pflugfelder SC, Ackerman, M. The effects of intranasal neurostimulation on tear production and clearance and conjunctival goblet cell secretion. Presented at the 8th International Conference on the Tear Film & Ocular Surface: Basic Science and Clinical Relevance, September 7-10, 2016; Montpellier, France.

6. Dieckmann G, Jamali A, Pondelis N, et al. In vivo confocal microscopy demonstrates intranasal neurostimulation-induced goblet cell alterations in patients with dry eye disease. Invest Ophthalmol Vis Sci. 2017;58(8):2694.

7. Watson M, Angjeli E, Orrick B, et al. Effect of the intranasal tear neurostimulator on meibomian glands. Invest Ophthalmol Vis Sci. 2017;58(8):4387.

8. Green KB, Kamat M, Franke M, et al. Tear total lipid concentration in patients with dry eye following intranasal neurostimulation. Invest Ophthalmol Vis Sci. 2017;58(8):2693.

9. Oyster Point Pharma announces positive results in ONSET-2 Phase 3 trial of OC-01 nasal spray for the treatment of the signs and symptoms of dry eye disease. Oyster Point. May 11, 2020. Accessed August 10, 2020.